BG08 Successful treatment of recalcitrant Darier disease with ustekinumab
Authors: Paula Finnegan, Cathal O’Connor, John Bourke
Journal: British Journal of Dermatology (2023)

Abstract Darier disease (DD) is a genodermatosis characterized by hyperkeratotic greasy papules in a seborrhoeic distribution. DD is caused by dominant mutations in ATP2A2, responsible for encoding the SERCA2 calcium pump. Currently, there are no licensed treatments for DD, but there is emerging evidence for the role of dysfunctional inflammation in DD. Our patient was a 49-year-old White woman with a history of recalcitrant DD involving extensive sheets of raw eroded skin. There was a strong family history of DD; her mother and maternal uncle had both died from sepsis related to DD. She suffered from recurrent superimposed skin infections, including methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas species and herpes simplex virus. Between 2019 and 2021, she required eight prolonged hospital admissions (average duration of stay 21 days; range 4–44) for intensive topical treatments (including potent topical steroids, emollients, topical antimicrobial agents and topical anaesthetic agents) and microbiology-guided systemic antimicrobial therapy [including oral co-amoxiclav, intravenous (IV) flucloxacillin, IV piperacillin–tazobactam, oral linezolid, IV daptomycin and oral valaciclovir]. She routinely required admission to the high-dependency unit for sepsis management, with multidisciplinary input from specialists in internal medicine, pain management, psychiatry and physiotherapy to enhance her recovery and optimize her associated comorbidities. Repeat biopsies were performed to confirm her diagnosis and rule out secondary viral infection or malignancy. Multiple systemic agents were trialled unsuccessfully, including acitretin, isotretinoin, alitretinoin, dapsone, ciclosporin and apremilast. Owing to the inflammatory presentation of her dermatosis and emerging evidence on the role of T helper 2-mediated inflammation in DD, the anti-interleukin (IL)-12/IL-23 agent ustekinumab was added to her regular treatment regimen. This successfully resulted in inducing disease remission within 5 months, with no further requirements for acute hospital admission or IV antimicrobial therapy in the year since initiation. Ustekinumab has never previously been reported for the treatment of DD in the literature. There have been individual reports of other inflammation-targeted agents such as IV methylprednisolone, immunoglobulin and ciclosporin, but treatment was poorly tolerated and relapse occurred following discontinuation. Penicillamine, doxycycline, oral contraceptive agents and oral magnesium have also been examined as potential therapeutic agents. Proinflammatory cytokines, in particular tumour necrosis factor-α and IL-6, have been associated with viral superinfection in DD, suggesting that systemic inflammation may closely relate to skin infections and disease activity in DD. In addition, cultured keratinocytes treated with IL-6 demonstrate reduced expression of ATP2A2. Ustekinumab may be a promising choice as a systemic immunomodulatory agent for DD. Future studies should examine the immune profile of patients with DD to inform therapeutic strategies.